How many ketogenic diet mechanisms of action can you name?

Ketogenic diet mechanisms of action

The ketogenic diet involves many mechanisms of action.

  1. Lowers blood sugar and insulin levels
  2. Decreases leptin
  3. Produces ketone bodies, which are an alternate source of energy, instead of glucose
  4. Ketone bodies have anti-seizure effects
  5. Changes neurotransmitter systems, including GABA, glutamate, and adenosine, as well as changes in ion channel regulation
  6. Increases mitochondrial function and production
  7. Increases circulating PUFA’s – neuroprotective (PUFA’s are Polyunsaturated fatty acids that include Omega-3’s and Omega-6’s. Some are referred to as essential fatty acids.)
  8. Decreases inflammation
    • Up regulation of glutathione peroxidase (an antioxidant)
    • Lowers levels of IL-1β and inflammatory cytokines
  9. Changes the gut microbiome
  10. Eliminates a lot of foods (speculative hypothesis)
  11. Changes DNA methylation and gene expression
  12. Increases autophagy – removal of damaged cell parts
  13. Increases nicotinamide adenine dinucleotide (NAD+)
  14. Activates Sirtuin genes

Could this complexity make it hard for exogenous ketones to replace the ketogenic diet for some indications? More research is needed.

Emerging research

Some recent studies relate to the gut microbiome as a mechanism of action for the ketogenic diet:

  • The role of gut microbes on brain health continues to strengthen. (1)

“In conclusion, our study identified 26 schizophrenia-associated bacterial species representing potential microbial targets for future treatment, as well as gut–brain modules, some of which may give rise to new microbial metabolites involved in the development of schizophrenia.”

Feng Zhu Et al.

  • The ketogenic diet improves lipid metabolism and blood pressure. (2)
  • The gut microbiome  plays a role in many illnesses, including metabolic disorders and mental health. Different foods and diets directly impact the bacteria living in our guts. Which foods are best for us?  (3)

“A calorie is NOT a calorie. A sugar is NOT a sugar. And now we know a fiber is NOT a fiber. Different fibers feed different bacteria, likely promoting different health effects.” 

Robert Lustig, MD

Exploring the gut microbiome, schizophrenia and bipolar disorder. (4)

Podcasts – hear Dr. Palmer in his own words

  • Interviewed by Paul Saladino, MD Mechanism discussion starts at 35:40. Neurotransmitters are mentioned at 19:00 & 25:00. Recommend listening from beginning, as Dr. Palmer builds a persuasive supportive arguments from the beginning
  • Interviewed by Shawn Baker, MD & Zach Bitters Gut microbiome discussion starts at 1:27:51. This podcast complements the one before and covers different aspects.

Research on ketogenic diet mechanisms in action

Seminal research studies include:

  • Bough, K. J., & Rho, J. M. (2007). Anticonvulsant Mechanisms of the Ketogenic Diet. Epilepsia, 48(1), 43–58.
  • Rho, J. M., & Sankar, R. (2008). The ketogenic diet in a pill: Is this possible? Epilepsia, 49 Suppl 8(Suppl 8), 127–133.
  • Masino, S. A., & Rho, J. M. (2012). Mechanisms of Ketogenic Diet Action. In J. L. Noebels, M. Avoli, M. A. Rogawski, R. W. Olsen, & A. V. Delgado-Escueta (Eds.), Jasper’s Basic Mechanisms of the Epilepsies (4th ed.). Retrieved from

Recent research footnotes

  1. Zhu, F., Ju, Y., Wang, W., Wang, Q., Guo, R., Ma, Q., … Ma, X. (2019). Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus. BioRxiv, 774265.
  2. Miyamoto, J., Ohue-Kitano, R., Mukouyama, H., Nishida, A., Watanabe, K., Igarashi, M., … Kimura, I. (2019). Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions. Proceedings of the National Academy of Sciences, 201912573.
  3. Patnode, M. L., Beller, Z. W., Han, N. D., Cheng, J., Peters, S. L., Terrapon, N., … Gordon, J. I. (2019). Interspecies Competition Impacts Targeted Manipulation of Human Gut Bacteria by Fiber-Derived Glycans. Cell, 179(1), 59-73.e13.
  4. Clay, H. B., Sillivan, S., & Konradi, C. (2011). Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. International Journal of Developmental Neuroscience : The Official Journal of the International Society for Developmental Neuroscience, 29(3), 311–324.

Citation library on

For a more extensive list of studies, visit Cecile’s citation library “Keto for Psych” on

With permission, I’ve added most of the research from to this library. However, Dr. Palmer was not involved in the choice and categorization of research beyond that.

Since my background is in business and economics, we’d appreciate any help with tagging and adding research!  


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